Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice

Abstract

Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7− and α4β7+ lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer’s patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46− group 3 ILCs in wild-type and even in Il7−/− mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer’s patches development by targeting lymphoid progenitor cells during fetal and adult life.

IL-15 sustains IL-7R-independent ILC2 and ILC3 development

“…1b). Consistent with prior reports618192021, the total numbers of all siLP ILC subsets except NK cells and ILC1 were reduced (Fig. 1c).…”

“…As ILC2 have not been reported in Il7 −/− or Il7ra −/− mice202127282930, we wondered if siLP ILC2 from Il7ra −/− mice had an altered cell-surface phenotype. As previously reported20 we noted three populations within siLP GATA3 hi ILC2 in WT and Il7ra −/− mice: ST2 + KLRG1 + ILC2, ST2 − KLRG1 + ILC2, and ST2 − KLRG1 − ILC2 (Fig.…”

“…A previous report demonstrated that Il7 −/− NKp46 + ILC3 were unable to generate IL-22 (ref. 19), while a recent report showed that bulk Il7 −/− ILC3 were able to produce significantly more IL-22 after stimulation with IL-23 in vitro 21. To assess both IL-17 and IL-22 production, we stimulated cells with IL-1β and IL-23, and found that all subsets of ILC3 were equally capable to produce IL-22, but had moderately impaired ability to produce IL-17a.…”

A functional DC cross talk promotes human ILC homeostasis in humanized mice

“…Because Flt3L regulates early DC precursors and homeostasis [22][23][24][25][26] (Figure 1; supplemental Figure 2), an improved myeloid compartment may provide a richer human cytokine environment, 51 thus indirectly supporting ILC survival and proliferation. This mechanism underlies DC transpresentation of IL-15 to mouse and human NK cells.…”

“…[22][23][24][25] We recently reported a humanized mouse model in which Flt3L-mediated enhancement of human DC numbers resulted in improved human NK cell homeostasis. 26 In this report, we generate and characterize a novel BALB/c Rag2…”